Compounds of the formula (II) wherein R1, R2, R3, R4, and R5 are as set forth herein, pharmaceutical compositions containing them, and their use in treating urinary incontinence....http://www.google.com/patents/US7019021?utm_source=gb-gplus-sharePatent US7019021 - Compounds and methods for treating urinary incontinence

(i) 2-(6-chloro-3-dimethylamino-2-methylphenylimino)imidazolidine, and

(j) 2-(6-chloro-3-phthalimidophenylimino)imidazolidine,

or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising:

(a) a compound selected from the group consisting of:

2-(3-dimethylamino-2-methylphenylimino)imidazolidine,

2-(6-bromo-3-dimethylamino-2-methylphenylimino)imidazolidine,

2-(5-amino-2-chloro-4-dimethylamino-2-methylphenylimino)imidazolidine, and

2-(3-amino-2-methylphenylimino)imidazolidine,

or a pharmaceutically acceptable salt thereof, and

(b) one or more pharmaceutically acceptable excipients, adjuvants, carriers, or preservatives.

6. A pharmaceutical composition comprising 2-(3-dimethylamino-2-methylphenylimino)imidazolidine, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, adjuvants, carriers, or preservatives.

7. A pharmaceutical composition comprising a compound in accordance with claim 2, and one or more pharmaceutically acceptable excipients, adjuvants, carriers, or preservatives.

8. A pharmaceutical composition comprising a compound in accordance with claim 3, and one or more pharmaceutically acceptable excipients, adjuvants, carriers, or preservatives.

9. A pharmaceutical composition comprising:

(a) a compound selected from the group consisting of:

2-(3-dimethylamino-2-methylphenylimino)imidazolidine,

2-(6-bromo-3-dimethylamino-2-methylphenylimino)imidazolidine,

2-(2-methyl-3-phthalimidophenylimino)imidazolidine,

2-(3-acetylamino-6-chlorophenylimino)imidazolidine,

2-(3-amino-2-methylphenylimino)imidazolidine,

2-(3-amino-4,6-dibromo-2-methylphenylimino)imidazolidine,

2-(3-amino-4-methylphenylimino)imidazolidine,

2-(4,6-dibromo-3-dimethylamino-2-methylphenylimino)imidazolidine,

2-(4-bromo-3-dimethylamino-2-methylphenylimino)imidazolidine,

2-(6-chloro-3-dimethylamino-2-methylphenylimino)imidazolidine,

2-(6-chloro-3-phthalimidophenylimino)imidazolidine,

or a pharmaceutically acceptable salt thereof; and

(b) one or more pharmaceutically acceptable excipients, adjuvants, carriers, or preservatives.

R2 is —NR6R7, wherein R6 and R7 together with the nitrogen between them form a 5- or 6-membered, saturated or unsaturated ring containing 0, 1, or 2 additional heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, wherein each additional nitrogen atom is unsubstituted or substituted by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, or R6 and R7 together with the nitrogen between them form phthalimido;

R2 is —NR6R7, wherein R6 and R7 together with the nitrogen between them form a 5- or 6-membered, saturated or unsaturated ring containing 0, 1, or 2 additional heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, wherein each additional nitrogen atom is unsubstituted or substituted by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, or R6 and R7 together with the nitrogen between them form phthalimido;

R2 is —NR6R7, wherein R6 and R7 together with the nitrogen between them form phthalimido;

R3 is hydrogen, methyl, fluorine, chlorine, or bromine;

R4 is hydrogen; and

R5 is hydrogen, methyl, fluorine, or bromine;

or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising a compound in accordance with claim 18, and one or more pharmaceutically acceptable excipients, adjuvants, carriers, or preservatives.

23. A pharmaceutical composition comprising a compound in accordance with claim 19, and one or more pharmaceutically acceptable excipients, adjuvants, carriers, or preservatives.

24. A pharmaceutical composition comprising a compound in accordance with claim 20, and one or more pharmaceutically acceptable excipients, adjuvants, carriers, or preservatives.

25. A pharmaceutical composition comprising a compound in accordance with claim 21, and one or more pharmaceutically acceptable excipients, adjuvants, carriers, or preservatives.

Description

RELATED APPLICATIONS

This is a continuation of U.S. Ser. No. 09/536,728, filed Mar. 28, 2000, which is a division of prior application U.S. Ser. No. 09/227,944, filed Jan. 11, 1999, now U.S. Pat. No. 6,268,389 which is a continuation under 37 C.F.R. § 1.53(b) of prior application U.S. Ser. No. 08/913,900, filed Feb. 26, 1998, now abandoned pursuant to 35 U.S.C. § 371, claiming benefit, under 35 U.S.C. § 120, from PCT/EP96/01568. Each of these prior applications is incorporated by reference herein in their entireties.

BACKGROUND OF THE INVENTION

The present invention relates to the use of α1L-agonists for treating urinary incontinence, particularly stress incontinence.

The cause of stress incontinence in women is usually weakness of the pelvic floor, e.g. after numerous difficult births. However, it may also be due to nerve disorders of the pelvic floor, a congenitally short urethra or, occasionally, damage to the sphincter caused by surgery. The reduction in the oestrogen levels post-menopause further encourages stress incontinence.

The term stress incontinence refers to a sudden loss of urine, which is caused by incompetence of the bladder outlet during unobtrusive movement of the bladder as a result of interabdominal increases in pressure due to coughing, pressing, sneezing, heavy lifting, etc.

Surprisingly, it has been found that the α1L-subtype of the adrenergic receptor has a significant effect on the continence mechanism of urether tonicisation.

The invention relates to the use of α1L-adrenoceptor agonists for treating urinary incontinence, particularly stress incontinence, and for preparing drugs for treating urinary incontinence, particularly stress incontinence. It is particularly interesting to use amino imidazolines of general formula

R6 and R7 together with the nitrogen atom form a 5- or 6-membered saturated or unsaturated ring which may contain up to two further heteroatoms selected from oxygen, sulphur- or nitrogen, whilst each additional nitrogen atom may be substituted by C1-4-alkyl, preferably methyl;

or R6 and R7 together with the nitrogen atom form phthalimido;
or

R1 and R2 together form a fused pyrazole of formula

wherein R8 is C1-3-alkyl, preferably methyl;
or a fused thiadiazole of formula

Examples of alkyl within the above definitions, including those which are components of other groups, are branched or unbranched C1-6-alkyl groups, e.g. methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, isobutyl, sec.-butyl and tert.-butyl, n-pentyl, isopentyl, neopentyl, hexyl and isohexyl.

Cycloalkyl generally represents a saturated cyclic hydrocarbon group having 3 to 6 carbon atoms which may optionally be substituted with a halogen atom or several halogen atoms, a hydroxy group, an alkyl group, preferably methyl, which may be the same as or different from one another. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl.

Some of the imidazolines defined in general formula Ib are new. The invention therefore also relates to new substituted 2-phenylimino-imidazolidines, their use in pharmaceutical compositions and to processes for preparing them.

2-(Phenylimino)-imidazolidines, the preparation thereof and their use as pharmaceutical compositions are known, for example from German Patent Application Nos. DE-OS-19 29 950 and DE-OS-23 16 377, in which the hypotensive properties of the compounds described are particularly emphasised.

New substituted 2-(phenylimino)-imidazolidines of general formula II

have surprising pharmacological properties and are particularly suitable for treating urinary incontinence.

R6 and R7 together with the nitrogen atom form a 5- or 6-membered saturated or unsaturated ring which may contain up to two additional heteroatoms selected from the group of oxygen, sulphur or nitrogen, whilst each additional nitrogen atom may be substituted by C1-4-alkyl, preferably methyl; or R6, and R7 together with the nitrogen atom from phthalimido;

Particular mention should be made of the following compounds, for example:

2-(3-dimethylamino-2-methylphenylimino)imidazolidine,

2-(6-bromo-3-dimethylamino-2-methylphenylimino)imidazolidine,

2-(5-amino-2-chloro-4-methylphenylimino)-imidazolidine and

2-(3-amino-2-methylphenylimino)-imidazolidine.

The compounds of general formula I and II may be prepared according to analogous processes known per se from the prior art. A selection of the preferred processes are shown in the following synthetic schemes with reference to concrete Examples.

The preferred processes for preparing the compounds according to the invention will be explained with reference to individual Examples.

The methylation of the starting material, 2-methyl-3-nitroaniline, may also be carried out analogously to the Leuckart-Wallach reaction using HCOOH/CH2O or using dimethylcarbonate instead of dimethylsulphate.

Compound 2 can be prepared by bromination of compound 1 under conventional reaction conditions

The following synthetic scheme illustrates the preparation of compounds 2, 3 and 4

Other alternative methods of synthesis are illustrated below.

Compound 5 and compounds of similar structure can be prepared analogously to a method described by N. R. Ayyangar (Synthesis 1987, 64).

EXAMPLE 12-(3-Dimethylamino-2-methylphenylimino)imidazolidine

1st Step:

83.6 g of 2-methyl-3-nitroaniline, 190 g of K2CO3 and 260 ml of water are together heated to 100° C. 27 ml of dimethylsulphate are added dropwise over 1 hour, then the mixture is heated for a further hour. After cooling to ambient temperature, the top layer is removed and the aqueous phase remaining is extracted four times with ether.

The combined ether extracts are combined with the upper layer, dried with MgSO4 and evaporated down in vacuo. 73 g of N,N-dimethyl-2-methyl-3-nitroaniline are obtained.

2nd Step:

73 g of N,N-dimethyl-2-methyl-3-nitroaniline are dissolved in 800 ml of methanol and hydrogenated at 20° C. under 5 bar of hydrogen using Raney nickel as catalyst. 57 g of 3-dimethylamino-2-methylaniline are obtained.

3rd Step:

57 g of 3-dimethylamino-2-methyl-aniline, 1.15 litres of acetone, 36.6 g of KSCN and 43.8 ml of benzoylchloride are refluxed together for 3 hours. After cooling to ambient temperature the reaction mixture is poured onto 2.4 kg of crushed ice. The precipitate obtained is heated to 60° C. for 2 hours together with 85 g of KOH, 85 ml of water and 255 ml of ethanol. After the addition of 850 ml of water the ethanol is distilled off under reduced pressure. After the resulting precipitate has been worked up, 72 g of N-(3-dimethylamino-2-methylphenyl)-thiourea are obtained.

4th Step:

72 g of the thiourea from Step 3 are taken up in 345 ml of methanol and after the addition of 22.6 ml of methyliodide the mixture is refluxed for 2 hours. The resulting solution is evaporated down under reduced pressure; 120 g of N-(3-dimethylamino-2-methylphenyl)-S-methyl-isothiourea hydroiodide are obtained.

5th Step:

120 g of the thiourea from Step 4 in 350 ml of methanol are combined with 34.4 ml of 1,2-diaminoethane and refluxed for 17 hours. The reaction mixture is then evaporated down in vacuo and the residue is taken up in water. The pH is adjusted to 7 using dilute hydrochloric acid. The aqueous phase is extracted 3 times with ethyl acetate. Then the aqueous phase is made alkaline with 5N NaOH and extracted a further 3 times with ethyl acetate, these extracts are combined, dried with MgSO4 and evaporated down in vacuo. An oil is obtained which is chromatographed over silica gel (eluant toluene, dioxane, ethanol, ammonia 10:8:3:1=“Super-T”).

17.9 g of 2-(3-dimethylamino-2-methylphenyl-imino)-imidazolidine are obtained.

Melting point 116–118° C.

EXAMPLE 22-(6-Bromo-3-dimethylamino-2-methylphenylimino)imidazolidine

6.55 g of 2-(3-Dimethylamino-2-methylphenyl-imino)-imidazolidine are dissolved in 75 ml of chloroform and 1.53 ml of bromine are added, with stirring, at 0° C. After 2 hours at 0° C. the solution is evaporated down under reduced pressure and the residue thus obtained is mixed with dilute hydrochloric acid. The aqueous solution is extracted twice with ether, then the aqueous phase is made alkaline with dilute NaOH and extracted three more times with ether. The combined ether extracts are evaporated down under reduced pressure and the residue remaining is worked up by chromatography (silica gel, eluant “Super-T” (Example 1)).

3.4 g of 2-(6-bromo-3-dimethylamino-2-methyl-phenylimino)-imidazolidine are obtained, Mp. 157–158° C., as a white powder.

The following compounds were prepared analogously to the processes described:

The corresponding hydrobromides and hydrochlorides are preferred as the acid addition salts.

Pharmaceutical compositions comprising the compounds described may be used in the form of capsules, suppositories, solutions, syrups, emulsions or dispersible powders. Corresponding tablets may be obtained, for example, by mixing the active substance or substances with known excipients such as inert diluents, e.g. calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc, and/or agents for obtaining delayed release, such as carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also consist of several layers.

Coated tablets may be produced accordingly, by coating cores made analogously to the tablets with agents conventionally used for tablet coating, e.g. collidone or shellac, gum arabic, talc, titanium dioxide or sugar. In order to achieve delayed release or prevent incompatibilities, the core may also consist of several layers. Similarly, the tablet coating may consist of several layers in order to achieve delayed release, and the excipients mentioned for the tablets may be used.

Syrups of the active substances or combinations of active substances according to the invention may additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents, e.g. condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

Injectable solutions are prepared in the usual way, e.g. by adding preservatives such as p-hydroxybenzoates or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid and are then transferred into injection vials or ampoules.

The capsules containing the active substance or combination of active substances may be prepared, for example, by mixing the active ingredients with inert carriers such as lactose or sorbitol and packaging the mixture in gelatine capsules.

Suitable suppositories may be produced, for example, by mixing with carriers provided for this purpose such as neutral fats of polyethyleneglycol or derivatives thereof.

For transdermal application the active substances according to the invention may be incorporated in suitable carriers (plasters), e.g. made of polyacrylates. Suitable adjuvants may be used in order to increase the release rate.

For oral administration a dosage of 1 to 50 mg is proposed as a therapeutically single dose.

EXAMPLE ATablets

2-(3-Dimethylamino-2-methylphenylimino)-

10 mg

imidazolidine.HBr

Lactose

65 mg

Corn starch

125 mg

sec.Calcium phosphate

40 mg

Soluble starch

3 mg

Magnesium stearate

4 mg

Colloidal silica

4 mg

Total

251 mg

Preparation:

The active substance is mixed with some of the excipients, kneaded intensively with an aqueous solution of the soluble starch and granulated with a sieve in the usual way. The granules are combined with the remaining excipients and compressed into tablet cores weighing 250 mg which are then coated in the usual way using sugar, talc and gum arabic.

EXAMPLE BAmpoules

2-(3-Dimethylamino-2-methylphenylimino)-

1.0

mg

imidazolidine.HBr

Sodium chloride

18.0

mg

Sufficient distilled water to make up to

2.0

ml

Preparation:

The active substance and sodium chloride are dissolved in water and transferred into glass ampoules under nitrogen.

EXAMPLE CDrops

2-(3-Dimethylamino-2-methylphenylimino)-

0.02

g

imidazolidine.HBr

Methyl p-hydroxybenzoate

0.07

g

Propyl p-hydroxybenzoate

0.03

g

Sufficient demineralised water to make up to

100

ml

EXAMPLE DInjectable Solution

2-(3-Dimethylamino-2-methylphenylimino)-

1.5 parts

imidazolidine.HBr

Sodium salt of ethylenediamine tetraacetic acid

0.2 parts

Sufficient distilled water to make up to

100.0 parts

Preparation:

The active substance and the sodium salt of ethylenediamine tetraacetic acid are dissolved in sufficient water and topped up to the desired volume with water. The solution is filtered to remove any suspended particles and transferred into 2 ml ampoules under aseptic conditions. Finally, the ampoules are sterilised and sealed. Each ampoule contains 20 mg of active substance.

One advantage of the compounds described is that they act primarily on the urethra and have little or no effect on the cardiovascular system.

The selective pharmacological activity of the compounds according to the invention is demonstrated by the compound of Example 2-2-(6-bromo-3-dimethylamino-2-methylphenylimino)-imidazolidine—and a comparison compound, phenylephrine, by measuring the intraluminal pressure of the urethra and blood pressure in the rabbit.

Female Japanese white rabbits (weighing 3.0 to 3.5 kg) are anaesthetised with urethane (1 g/kg i.p.). A polyethylene cannula is inserted in the urinary bladder by means of a small incision. The changes in the intraluminal pressure are recorded by means of balloon in the urethra which contains about 1.5 ml of water at 37° C. The intraurethral pressure is recorded on a polygraph by means of a pressure-voltage transducer.

The neck is opened up and the carotid artery is cannulated in order to measure the blood pressure and at the same time the trachea is intubated in order to maintain breathing. The changes in blood pressure are recorded on a polygraph by means of a pressure-voltage transducer. Heart rate is measured using a tachometer.

Phenylephrine and the compound of Example 2 are introduced into the Vena femoralis i.v. through a polyethylene cannula. Dosages of 30 μg/kg of phenylephrine are compared with 10 μg/kg of the compound of Example 2.

Compared with phenylephrine the compound of Example 2 according to the invention exhibits a potency which is higher by a factor of 2.73 with regard to the contraction of the urethra and with a duration of effect which is longer by a factor of 4.3. By comparison, the increase in blood pressure with the compound according to the invention is only 1.39 times that of the comparison compound phenylephrine. It is notable that the increase in blood pressure is prolonged only to an insignificant degree (by a factor of 1.17) compared with phenylephrine. These experiments show that the compounds according to the invention have a selective effect on the urethra. Being selective α1L-adrenoreceptor agonists, the compounds according to the invention are suitable for treating problems of urinary incontinence, particularly for treating stress incontinence.